Cyclopropyl N-hydroxyurea and N-hydroxyacetamides which inhibit lipoxygenase

ABSTRACT

Compounds of the formula ##STR1## wherein A is C1 to C3 alkylene, Ar is phenyl or styryl, R is halosubstituted C1 to C3 alkyl, NHR&#39; or ##STR2## R&#39; is hydrogen or C2 to C8 alkytthioalkyl, n is an integer of from 1 to 4 and p is an integer of from 2 to 5, with the proviso that when R&#39; is hydrogen then Ar is styryl, and the pharmaceutically acceptable salts thereof, inhibit the enzyme lipoxygenase and are useful in treating allergy and inflammatory and cardiovascular conditions for which the action of lipoxygenase has been implicated. These compounds form the active ingredient in pharmaceutical compositions for treating such conditions.

This application is a 371 of PCT US92/08979 filed Oct. 27, 1992.

BACKGROUND OF THE INVENTION FIELD OF THE INVENTION

This invention relates to novel cyclopropyl N-hydroxyurea endN-hydroxyacetamide derivatives. The compounds of the present inventioninhibit the action of the enzyme lipoxygenase end are useful in thetreatment or alleviation of inflammatory diseases, allergy endcardiovascular diseases in mammals. This invention also relates topharmaceutical compositions comprising such compounds end to the use ofsuch compounds in treating inflammatory diseases, allergy endcardiovascular diseases in mammals. This invention further relates tomethods of making such compounds.

Arachidonic acid is known to be the biological precursor of severalgroups of endogenous metabolites, prostaglendins including prostacydins,thromboxenes end leukotrienes. The first step of arachidonic acidmetabolism is the release of arachidonic acid end related unsaturatedfatty acids from membrane phospholipids, via the action ofphospholipase. Free fatty acids are then metabolized either bycyclooxygenase to produce the prostaglendins end thromboxenes or bylipoxygenase to generate hydroperoxy fatty acids which may be furtherconverted to the leukotrienes. Leukotrienes have been implicated in thepatiophysiology of inflammatory diseases, including rheumatoidarthritis, gout, asthma, ischemia reperfusion injury, psoriasis endinflammatory bowel disease. Any drug that inhibits lipoxygenase isexpected to provide significant new therapy for both acute end chronicinflammatory conditions.

Several review articles on lipoxygenase inhibitors have been reported(See H. Masamune et ed., Ann. Rep. Med. Chem., 24, 71-80 (1989) end B.J. Fitzsimmons et al., Leukotrienes and Lipoxygenases, 427-502 (1989).

Compounds of the same general class as the compounds of the presentinvention are disclosed in EP 279263 A2, EP 196184 A2, EP 436199 A, JP(Kohyo) 502179/88, JP (Appln.) 105648/90 and U.S. Pat. No. 4,822,809.

SUMMARY OF THE INVENTION

The present invention provides novel cyclopropyl N-hydroxyurea andN-hydroxyacetamide derivatives of the following formula and theirpharmaceutically acceptable salts. ##STR3## wherein A is C1 to C3alkylene, Ar is phenyl or styryl, R is halosubstituted C1 to C3 alkyl,NHR' or ##STR4## R' is hydrogen or C2 to C8 alkytthioalkyl, n is aninteger of from 1 to 4 and p is an integer of from 2 to 5, with theproviso that when R' is hydrogen then Ar is styryl.

This invention also concerns pharmaceutical compositions comprising apharmaceutically acceptable carrier or diluent and a compound of theinvention or a pharmaceutically acceptable salt thereof. This inventionfurther concerns methods of treating inflammatory diseases, allergy andcardiovascular diseases in mammals comprising administration of suchcompounds or compositions.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

As used herein, the following definitions are used.

"Halo" and "halogen" mean radicals derived from the elements fluorine,chlorine, bromine and iodine.

"Alkyl" means straight or branched saturated hydrocarbon radicals, forexample, methyl, ethyl, n-propyl and isopropyl.

"Halosubstituted alkyl" refers to an alkyl radical as described abovesubstituted with one or more halogen radicals, for example,chloromethyl, bromoethyl and trifluoromethyl.

"Alkylene" means straight or branched alkene radicals, for example,methylene, 1,2-ethylene, 1,3-propylene and 1,2-propylene.

"Alkylthioalkyl" means a group of the structure -RSR wherein R is alkylas defined above, for example, methylthiomethyl, methylthioethyl,methylthiopropyl, ethylthioethyl and propylthiomethyl.

This invention includes pharmaceutical compositions for treatment ofinflammatory diseases, allergy and cardiovascular diseases in a mammalwhich comprises a pharmaceutically acceptable carrier or diluent and acompound of the above formula or a pharmaceutically acceptable saltthereof.

This invention also includes pharmaceutical compositions for inhibitingthe lipoxygenase in mammal which comprises a pharmaceutically acceptablecarrier and a compound of the above formula or a pharmaceuticallyacceptable salt thereof.

The novel compounds of this invention may be prepared as shown in thereaction scheme described below. ##STR5##

In the above scheme, A and R are as previously defined and Q is ##STR6##wherein Ar is phenyl or styryl.

The compounds of the invention are prepared according to the reactionsteps explained in detail as follows.

The starting materials used in the procedure of the above reactionscheme may be prepared from commercially available compounds or knowncompounds according to standard methods known in the art.

In the first step, an alcohol (II) can be prepared via reduction of thecorresponding ketone (I) with suitable reducing agent(s). Subsequently,the corresponding hydroxylamine (III) can be prepared by treating saidalcohol with N,O-bis(tert-butoxycarbonyl)hydroxylamine underMitsunobu-type reaction conditions followed by acid-catalyzed hydrolysisof the N,O-protected intermediate product (sea JP (Kokai) 45344/89).

For example, ketone (I) is treated with tetrahydrofuran (THF) and areducing agent (LiAIH₄, LiAIH(OC(CH₃)₃)₃ and the like) in areaction-inert solvent. Preferred solvents include benzene, toluene, Et₂O, THF and methylene chloride. The reaction is usually carded out in thetemperature range of from about -80° to about reflux temperature, withreaction times generally from several minutes to about 24 hours. Thehydroxylamine thus obtained can be isolated by standard methods andpurification can be achieved by conventional means, such as byrecrystallization end chromatography.

The acetamides (IV) of the present invention can be prepared by treatingthe hydroxylamine with substituted acetyl chloride. For example, thehydroxylamine is reacted with acetyl chloride or the like in areaction-inert solvent in the presence of a suitable base. Preferredbases include trimethylamine and pyridine; sodium hydride can also beused. Suitable solvents include methylene chloride, chloroform, THF,benzene end toluene. The reaction is usually carried out in thetemperature range of from about 0° C. to about room temperature, withreaction times generally from about 30 minutes to several hours. Thefinal product acetamide (IV) can be isolated and purified byconventional means, such as by recrystallization and chromatography.

The ureas (IV) of the present invention can be prepared by treating thehydroxylamine (III) with a suitable isocyanate corresponding to thedesired final product in a reaction-inert solvent. The reaction isusually carried out in the range of from room temperature through toreflux temperature. Suitable solvents which do not react with thehydroxylamine and/or isocyanate include, for example, THF, dioxane,methylene chloride and benzene. Preferred isocyanates includechloropropyl isocyanate, isocyanate propionic acid and trimethylsilylisocyanate. The final product urea (IV) can be isolated and purified byconventional means, such as by recrystallization and chromatography.

The pharmaceutically acceptable salts of the novel compounds of thepresent invention are readily prepared by contacting said compounds witha stoichiometric amount of, in the case of a non-toxic cation, anappropriate metal hydroxide or alkoxide or amine in either aqueoussolution or a suitable organic solvent, or, in the case of a non-toxicacid salt, an appropriate mineral or organic acid in either aqueoussolution or a suitable organic solvent. The salt may then be obtained byprecipitation or by evaporation of the solvent.

While the compounds of the present invention produced by the methodsoutlined above are racemic mixtures, they can be resolved into opticallyactive isomers via known processes.

The compounds of this invention inhibit the activity of the enzymelipoxygenase. This inhibition has been demonstrated by an assay usingrat peritoneal cavity-resident calls which determines the effect of saidcompounds on the metabolism of arachidonic acid.

All of the compounds of Examples 1 to 4 were tested according to themethods described in "Synthesis of leukotrienes by peritonealmacrophages," Jap. J. Inflammation, 7, 145-150 (1987), and were shown tobe lipoxygenase inhibitors, exhibiting IC₅₀ values in the range of about0.186 to about 24.5 μM, for lipoxygenase inhibition.

The ability of the compounds of the present invention to inhibitlipoxygenase makes them useful for controlling the symptoms induced bythe endogenous metabolites arising from arachidonic acid in a mammaliansubject. The compounds are therefore valuable in the prevention andtreatment of such disease states in which the accumulation ofarachidonic acid metabolites are the causative factor, e.g., allergicbronchial asthma, skin disorders, rheumatoid arthritis, osteoarteritisand thrombosis.

The compounds of the invention and their pharmaceutically acceptablesalts are of particular use in the treatment or alleviation ofinflammatory diseases, allergy and cardiovascular diseases in a humansubject as well in the inhibition of lipoxygenase.

Methods of Administration

For treatment of the various conditions described above, the compoundsof the invention and their pharmaceutically acceptable salts can beadministered to a human subject either alone or, preferably, incombination with pharmaceutically acceptable carriers or diluents in apharmaceutical composition, according to standard pharmaceuticalpractice. A compound can be administered via a variety of conventionalroutes of administration including orally, parenterally and byinhalation. When the compounds are administered orally, the dose rangewill generally be from about 0.1 to about 20 mg/kg/day, based on thebody weight of the subject to be treated, preferably from about 0.1 toabout 1.0 mg/kg/day in single or divided doses. If parenteraladministration is desired, then an effective dose will generally be fromabout 0.1 to about 1.0 mg/kg/day. In some instances it may be necessaryto use dosages outside these limits, since the dosage will necessarilyvary according to the age, weight and response of the individual patientas well as the severity of the patient's symptoms and the potency of theparticular compound being administered.

For oral administration, the compounds of the invention and theirpharmaceutically acceptable salts can be administered, for example, inthe form of tablets, powders, lozenges, syrups or capsules, or as anaqueous solution or suspension. In the case of tablets for oral use,carriers which are commonly used include lactose and corn starch.Lubricating agents such as magnesium stearate are commonly added. In thecase of capsules, useful diluents are lactose and dried corn starch.When aqueous suspensions are required for oral use, the activeingredient is combined with emulsifying and suspending agents. Ifdesired, certain sweetening and/or flavoring agents can be added.

For intramuscular, intraperitoneal, subcutaneous and intravenous use, asterile solution of the active ingredient is usually prepared, and thepH of the solutions should be suitably adjusted and buffered. Forintravenous use, the total concentration of solute should be controlledto make the preparation isotonic.

EXAMPLES

The present invention is illustrated by the following examples. However,it should be understood that the invention is not limited to thespecific details of these examples.

Proton nuclear magnetic resonance spectra (NMR) were measured at 270 MHzunless otherwise indicated and peak positions are expressed in parts permillion (ppm) downfield from tetramethylsilane. The peak shapes aredenoted as follows: s, singlet; d, doublet; t, triplet; q, quartet; m,multiplet; br, broad.

EXAMPLE 1 N-hydroxy-N-[(2-trans-styrylcyclopropyl)methyl]urea ##STR7##

To a stirred solution ofN,O-bis(t-butoxycarbonyl)-N-[(2-trans-styryl-1-cyclopropyl)methyl]hydroxylamine(3.7 g, 9.5 mM) in methylene chloride (30 ml) was added trifluoroaceticacid (5.42 g) dropwise at 5° C. After stirring for 1.5 hours, thevolatiles were removed in vacuo. Saturated aqueous sodium bicarbonate(50 ml) was added, and the whole extracted with ethyl acetate (2×100 ml,50 ml). The organic layer was washed with water (100 ml) and brine (100ml), then was added over magnesium sulfate and evaporated in vacuo toafford 1.94 g (78.7% yield) of the corresponding hydroxylamine.

To a stirred solution of said hydroxylamine (1.94 g, 10.26 mM) in dryTHF (20 ml) was added trimethylsilyl isocyanate (1.71 g, 13.34 mM) atroom temperature under a nitrogen atmosphere. After stirring overnight,methanol (20 ml) was added to quench the reaction, volatiles wereremoved in vacuo, and the resulting solid was recrystallized from ethylacetate/n-hexane, providing 0.84 g (38% yield) of the desired product ascolorless crystals, m.p. 138°-139° C. (dec.).

IR (nujol): 3460, 1615, 1575, 1155, 990, 950, 740, 690.

NMR (CDCl₃): 9.05 (s, 1H), 7.32 (s, 5H), 6.44 (d, J=15.4 Hz, 1H), 5.78(dd, J=8.8, 15.4 Hz, 1H), 5.38 (br s, 2H), 3.54 (dd, J=6.6, 15 Hz, 1H),3.43 (dd, J=7.4, 15 Hz, 1H), 1.58 (m, 1H), 1.35 (m, 1H), 0.81 (m, 2H).

EXAMPLE 2 N-hydroxy-N'-(3-methylthiopropyl)-N-[(trans-2-phenylcyclopropyl)methyl]urea ##STR8##

To a stirred solution ofN'-(3-chloropropyl)-N-hydroxy-N-[(trans-2-phenyleyclopropyl)methyl]urea(0.79 g, 2.8 mM) in dry THF (10 ml) was added sodium thiomethoxide (0.5g, 16.7 mM) at room temperature. After stirring overnight, it was pouredinto saturated aqueous ammonium chloride. The whole was extracted withethyl acetate (2×120 ml). The extracts were washed with water and brine,then were dried and evaporated in vacuo. The product was recrystallizedfrom ethyl acetate/n-hexane, vacuum filtered and dried to furnish 0.82 g(35% yield) of the desired product, m.p. 103°-104° C.

IR (neat): 3.360, 1590, 1550, 1255, 1160, 1110, 750, 690.

NMR (DMSO-d6): 9.23 (s, 1H), 7.14 (m, 5H), 6.97 (t, J=6.2 Hz, 1H), 3.35(m, 2H), 3.11 (q, J=6.6 Hz, 2H), 2.42 (t, J=6.6 Hz, 2H), 2.04 (s, 3H),1.85 (m, 1H), 167 (m, 2H), 1.33 (m, 1H), 0.88 (m, 2H).

EXAMPLE 3α-chloro-N-hydroxy-N-[(trans-2-phenylcyclopropyl)methyl]acetamide##STR9##

To a stirred solution ofN-[(trans-2-phenylcyclopropyl)methyl]-N-hydroxylamine (3.26 g, 20 mM) inmethylene chloride (50 ml) was added chloroacetyl chloride (4.52 g, 40mM) and triethylamine (4.04 g, 40 ml) at room temperature. Afterstirring for 5 hours, it was poured into saturated aqueous sodiumbicarbonate. The whole was extracted with chloroform (2×100 ml). Theextracts were washed with water and brine, then were added andevaporated in vacuo. Chromatographic purification (eluentchloroform:ethanol=15:1) of the residue provided 2 g (41.8% yield) ofthe desired product as a pale yellow oil.

IR (neat): 3200, 1640, 1500, 1245, 1175, 1090, 1030, 925.

NMR (DMSO-d6): 10.09 (s, 1H), 7.10 (m, 5H), 4.40 (s, 2H), 3.57 (d, J=7.0Hz, 2H), 1.88 (m, 1H), 1.37 (m, 1H), 0.94 (m, 1H).

EXAMPLE 4N-hydroxy-N-[(trans-2-phenyl-1-cyclopropyl)methyl]-α-(1-pyrrolidino)acetamide##STR10##

To a stirred solution ofα-chloro-N-hydroxy-N-[(trans-2-phenylcyclopropyl)methyl]acetamide (0.75g, 3.13 mM) in THF (7 ml) was added pyrrolidine (0.29 g, 4.07 mM) atroom temperature. After stirring for 2 hours, volatiles were removed invacuo. Ethyl acetate and saturated aqueous sodium bicarbonate was addedto the residue and the whole was extracted with ethyl acetate. Theextracts were washed with brine then dried and evaporated in vacuo. Theresulting residue was triturated with diethylether and filtered toafford 0.532 g (62% yield) of the desired product as a colorless solid,m.p. 101°-102.5° C.

IR (nujol): 1650, 1260, 1180, 1160, 1020, 880, 755, 700.

NMR (DMSO-d6): 9.79 (s, 1H), 7.18 (m, 4H), 3.52 (d, J=6.6 Hz, 2H), 3.36(s, 2H), 2.50 (m, 4H), 1.88 (m, 1H), 1.66 (br s, 4H), 1.34 (m, 1H), 0.92(m, 2H).

We claim:
 1. A compound of the formula ##STR11## or a pharmaceuticallyacceptable salt thereof, wherein: A is C1 to C3 alkylene;Ar is phenyl; Ris halosubstituted C1 to C3 alkyl, NHR' or ##STR12## R' is C2 to C8alkylthioalkyl; n is an integer of from 1 to 4; and p is an integer offrom 2 to
 5. 2. A compound according to claim 1 wherein:Ar is phenyl;and R' is C2 to C8 alkylthioalkyl.
 3. A compound according to claim 1wherein:Ar is phenyl; and R is halosubstituted C1 to C3 alkyl.
 4. Acompound according to claim 1 wherein:Ar is phenyl; and R ispyrrolidinomethyl.
 5. A compound according to claim 1 selected from:N-hydroxy-N'-(3-methylthiopropyl)-N-[(trans-2-phenylcyclopropyl)methyl]urea;α-chloro-N-hydroxy-N-[(trans-2-phenylcyclopropyl)methyl]acetamide; andN-hydroxy-N-[(trans-2-phenyl-1-cyclopropyl)methyl]-α-(1-pyrrolidino)acetamide.6. A pharmaceutical composition for the treatment of allergy,inflammatory or cardiovascular conditions in a mammal comprising atherapeutically effective amount of a compound according to claim 1 or apharmaceutically acceptable salt thereof together with apharmaceutically acceptable carrier.
 7. A pharmaceutical composition forthe treatment of allergy, inflammatory or cardiovascular conditions in amammal comprising a therapeutically effective amount of a compoundaccording to claim 5 or a pharmaceutically acceptable salt thereoftogether with a pharmaceutically acceptable carrier.
 8. A method ofinhibiting lipoxygenase in a mammal comprising administering to saidmammal a lipoxygenase-inhibiting amount of a compound according to claim1 or a pharmaceutically acceptable salt thereof.
 9. A method ofinhibiting lipoxygenase in a mammal comprising administering to saidmammal a lipoxygenase-inhibiting amount of a compound according to claim5 or a pharmaceutically acceptable salt thereof.
 10. A method oftreating allergy or inflammatory or cardiovascular conditions in amammal comprising administering to said mammal a lipoxygenase-inhibitingamount of a compound according to claim 1 or a pharmaceuticallyacceptable salt thereof.
 11. A method of treating allergy orinflammatory or cardiovascular conditions in a mammal comprisingadministering to said mammal a lipoxygenase-inhibiting amount of acompound according to claim 5 or a pharmaceutically acceptable saltthereof.